The Variable Response to Teduglutide in Pediatric Short Bowel Syndrome: A Single Country Real-Life Experience.

OBJECTIVES: The glucagon-like peptide-2 analog Teduglutide has been shown to enhance intestinal absorption and decrease parenteral nutrition (PN) requirements in short bowel syndrome (SBS). As data in children is limited, we evaluated nationwide real-life experience and treatment outcome in children with SBS. METHODS: Longitudinal data of children treated with Teduglutide for ≥3 months was collected. Data included demographic and medical background, anthropometrics, laboratory assessments and PN requirements. Treatment response was defined as >20% reduction in PN requirement. RESULTS: The study included 13 patients [54% males, median (interquartile range {IQR}) age of 6 (4.7-7) years]. The most common SBS etiology was necrotizing enterocolitis (38%), and median (IQR) small bowel length was 20 (15-40) cm. Teduglutide treatment ranged between 3 and 51 months [median (IQR) of 18 (12-30) months], with 10 patients (77%) treated >1 year. Response to treatment was observed in 8 patients (62%), with a mean [±standard deviation (SD)] treatment duration of 5.9 (±3.2) months. Among responders, 2 patients were weaned off PN and additional 4 decreased PN needs by >40%. There was a median (IQR) reduction in PN volume/kg of 36% (15%-55%) and in PN energy/kg of 27% (6%-58%). Response was not associated with patients' background, and no correlation was found with bowel length or PN dependency at baseline. CONCLUSIONS: Real-life response to Teduglutide is highly variable among children with SBS. While most patients did reach 20% reduction in PN, less achieved further significant reduction or enteral autonomy. No predictive factors of response to treatment were identified, and large multicenter studies are needed to elucidate predictive factors and long-term outcome.

Prediction Models for Celiac Disease Development in Children From High-Risk Families: Data From the PreventCD Cohort.

BACKGROUND & AIMS: Screening for celiac disease (CD) is recommended in children with affected first-degree relatives (FDR). However, the frequency of screening and at what age remain unknown. The aims of this study were to detect variables influencing the risk of CD development and develop and validate clinical prediction models to provide individualized screening advice. METHODS: We analyzed prospective data from the 10 years of follow-up of the PreventCD-birth cohort involving 944 genetically predisposed children with CD-FDR. Variables significantly influencing the CD risk were combined to determine a risk score. Landmark analyses were performed at different ages. Prediction models were created using multivariable Cox proportional hazards regression analyses, backward elimination, and Harrell's c-index for discrimination. Validation was done using data from the independent NeoCel cohort. RESULTS: In March 2019, the median follow-up was 8.3 years (22 days-12.0 years); 135/944 children developed CD (mean age, 4.3 years [range, 1.1-11.4]). CD developed significantly more often in girls (P = .005) and in Human Leukocyte Antigen (HLA)-DQ2 homozygous individuals (8-year cumulative incidence rate of 35.4% vs maximum of the other HLA-risk groups 18.2% [P < .001]). The effect of homozygosity DR3-DQ2/DR7-DQ2 on CD development was only present in girls (interaction P = .04). The prediction models showed good fit in the validation cohort (Cox regression 0.81 [0.54]). To calculate a personalized risk of CD development and provide screening advice, we designed the Prediction application https://hputter.shinyapps.io/preventcd/. CONCLUSION: Children with CD-FDR develop CD early in life, and their risk depends on gender, age and HLA-DQ, which are all factors that are important for sound screening advice. These children should be screened early in life, including HLA-DQ2/8-typing, and if genetically predisposed to CD, they should get further personalized screening advice using our Prediction application. TRIAL REGISTRATION NUMBER: ISRCTN74582487 (https://www.isrctn.com/search?q=ISRCTN74582487).

Prevalence of elevated liver enzymes and comorbidities in children and adolescents with overweight and obesity.

AIM: We investigated the prevalence of elevated liver aminotransferases (ALT) and additional comorbidities in a large cohort of Israeli children and adolescents with overweight and obesity. METHODS: This study included data from medical records of 2- to 18-year-old children and adolescents, with body mass index (BMI) in the overweight or obesity range (WHO definitions), for whom ALT testing was performed. RESULTS: Overweight was present in 50 418 (10.7%) and obesity in 70 515 (15.0%). Elevated ALT, above 30 IU/L (0.51 µkat/L), was reported in 2245 (7.2%) of children with overweight and 5475 (16.8%) of children with obesity (P < .0001). Compared to children with overweight and obesity and ALT within normal range, children with elevated ALT were older (11.9 ± 4.2 vs 10.9 ± 4.2, P < .001), mostly male (68.0% vs 49.4%, P < .001) and had higher BMI (27.3 ± 6.1vs 24.0 ± 4.8, P < .001). They also had a more unfavourable cardiometabolic profile with significantly higher either systolic or diastolic blood pressure, total cholesterol and triglycerides, and had more than three criteria defining metabolic syndrome. CONCLUSION: In this large cohort, abnormally elevated ALT was present in a high number of individuals with overweight or obesity. The children and adolescents with abnormal ALT had higher BMI, were older, male and had more cardiometabolic risk factors.

Growth rate of coeliac children is compromised before the onset of the disease.

INTRODUCTION: Growth impairment has often been described in children who develop coeliac disease (CD). Based on data from the multicentre, longitudinal PreventCD study, we analysed the growth patterns of infants at genetic risk of CD, comparing those who developed CD by 6 years of age (CD 'cases', 113 infants) versus those who did not develop CD by 6 years (no CD 'controls', 831 infants). METHODS: Weight and length/height were measured using a longitudinal protocol. Raw measurements were standardised, computing z-scores for length/height and weight; a linear mixed model was fitted to the data in order to compare the rate of growth in the two cohorts. RESULTS: Neither cases nor controls had significant growth failure. However, when the mean z-scores for weight and height were analysed, there was a difference between the two groups starting at fourth month of life. When the growth pattern in the first year was analysed longitudinally using mixed models, it emerged that children who develop CD had a significantly lower growth rate in weight z-score (-0.028/month; 95% CI -0.038 to -0.017; p<0.001) and in length/height z-score (-0.018/month; 95% CI -0.031 to -0.005; p=0.008) than those who do not develop CD. When the whole follow-up period was analysed (0-6 years), differences between groups in both weight and length/height z-scores were confirmed. CONCLUSION: The growth of children at risk of CD rarely fell below 'clinical standards'. However, growth rate was significantly lower in cases than in controls. Our data suggest that peculiar pathways of growth are present in children who develop CD, long before any clinical or serological signs of the disease appear.

Noncoding deletions reveal a gene that is critical for intestinal function.

Large-scale genome sequencing is poised to provide a substantial increase in the rate of discovery of disease-associated mutations, but the functional interpretation of such mutations remains challenging. Here we show that deletions of a sequence on human chromosome 16 that we term the intestine-critical region (ICR) cause intractable congenital diarrhoea in infants1,2. Reporter assays in transgenic mice show that the ICR contains a regulatory sequence that activates transcription during the development of the gastrointestinal system. Targeted deletion of the ICR in mice caused symptoms that recapitulated the human condition. Transcriptome analysis revealed that an unannotated open reading frame (Percc1) flanks the regulatory sequence, and the expression of this gene was lost in the developing gut of mice that lacked the ICR. Percc1-knockout mice displayed phenotypes similar to those observed upon ICR deletion in mice and patients, whereas an ICR-driven Percc1 transgene was sufficient to rescue the phenotypes found in mice that lacked the ICR. Together, our results identify a gene that is critical for intestinal function and underscore the need for targeted in vivo studies to interpret the growing number of clinical genetic findings that do not affect known protein-coding genes.

Validation and impact of paediatric malnutrition screening tool in hospitalised children on awareness of medical staff and health-related outcomes.

AIMS: This study aimed to evaluate the use of the Screening Tool for the Assessment of Malnutrition in Paediatrics (STAMP) among children admitted in a paediatric hospital, and assess its impact on the nutritional status awareness among the medical staff and on health outcomes at discharge. METHODS: STAMP performed by nurses on admission was compared with full nutritional assessment performed by a dietitian. Area under the receiving operating characteristic (AUROC) curve was used to evaluate validity of the tool. To assess how the tool affected awareness among the staff, information on nutritional status was compared prior to and following the intervention period. Therewith, health outcomes at discharge were compared for the children who had been screened by STAMP and the children who had not. RESULTS: The analysis was performed for a total of 60 children (38 boys, 63%). The mean age was 7.8 ± 4.7 years. Malnutrition was found in 16% of patients, segregating equally between acute and chronic malnutrition. Sensitivity, specificity, positive predictive value and negative predictive value were 95.7% (95% confidence interval, CI = 85.75-98.83%), 76.9% (95% CI = 49.74-91.82%), 93.7 and 83.3, respectively. AUROC was 0.863 (95% CI = 0.72-1). There was no difference either in malnutrition awareness among the medical staff before and after the intervention period or in health outcomes at discharge. CONCLUSIONS: STAMP is a valid tool for malnutrition screening in hospitalised children; however, its use does not influence admitted patients' nutritional status awareness among the medical staff nor their outcomes at discharge.

Decreased Fecal Calprotectin Levels in Cystic Fibrosis Patients After Antibiotic Treatment for Respiratory Exacerbation.

OBJECTIVES: In all patients with cystic fibrosis (CF), gastrointestinal (GI) tract CF transmembrane conductance regulator dysfunction occurs early in life. The identical pathophysiological triad of obstruction, infection, and inflammation causes disease of the airways and in the intestinal tract (CF enteropathy). Mucus accumulation within GI tract is a niche for abnormal microbial colonization, leading to dysbiosis. Fecal calprotectin (FC) is a neutrophil cytosolic protein released during apoptosis and necrosis and reflects inflammatory status. Systemic antibiotic treatment for pulmonary exacerbations has been shown to improve systemic inflammatory markers and serum and sputum calprotectin. Antibiotic treatment aimed at pulmonary complaints may improve GI tract inflammatory status. We hypothesized that high levels of FC present during pulmonary exacerbation are due, in part, to multiorgan dysbiosis and thus should diminish with systemic antibiotic treatment. METHODS: This prospective pilot study enrolled 14 patients with CF, with no current GI symptoms. FC levels and lung function were measured at the beginning and end of systemic antibiotic treatment. RESULTS: Compared to preantibiotic treatment baseline values, end of treatment FC levels declined significantly after antibiotic treatment, P = 0.004 and similarly, there was significant improvement in forced expiratory volume in 1 second, P = 0.002. CONCLUSIONS: High levels of FC during respiratory exacerbation may reflect a systemic exacerbation rather than solely pulmonary. Antibiotic treatment lowered the FC levels possibly by its impact on the intestinal microbiome.

Long-term Extent Change of Pediatric-Onset Ulcerative Colitis.

BACKGROUND: Data describing extent change (progression or regression) in pediatric-onset ulcerative colitis (UC) are scarce. GOAL: We aimed to describe extent change in pediatric-onset UC during long-term follow-up and to assess predictors of extent change. STUDY: Medical charts of pediatric-onset UC patients with at least 5-year follow-up were analyzed retrospectively. Disease extent was determined using the Paris classification. It was examined at diagnosis and during follow-up at different time points. The impact of possible predictors on extent change including age at diagnosis, gender, clinical manifestations, disease, severity indices, and different therapeutic regimens during disease course was assessed. RESULTS: Patients (n=134, 55% males) were followed for a median duration of 13.1 (range, 5 to 28) years. Median age at diagnosis was 13.1 (range, 2 to 17.8) years. Of 134 patients, 40.5% had extensive or pancolitis, 33.5% left-sided colitis, and 26% had proctitis at diagnosis. On follow-up (n=117), 45% had unchanged disease extent, 35% experienced extent progression, whereas 20% experienced regression of disease extent. The multivariate Cox models demonstrated that among children with left-sided disease at diagnosis, presence of extraintestinal manifestations (hazard ratio, 5.19; P=0.022), and higher pediatric UC activity index (hazard ratio, 8.77; P=0.008) were associated with extent progression to extensive disease. Predictors of extent regression have not been identified. CONCLUSIONS: Disease extent changes significantly over time in pediatric-onset UC. In our cohort, presence of extraintestinal manifestation and higher pediatric UC activity index score at diagnosis were associated with progression from limited to extensive disease during follow-up.

Incidence of Bowel Surgery and Associated Risk Factors in Pediatric-Onset Crohn's Disease.

BACKGROUND: Data describing the incidence and the risk factors for surgical interventions in pediatric Crohn's disease (CD) is inconsistent. Our aim was to describe the rates of intestinal surgery and to identify associated risk factors in a large cohort of children with CD. METHODS: Medical charts of 482 children with CD from the Schneider Pediatric Inflammatory Bowel Disease cohort who were diagnosed between 1981 and 2013 were carefully reviewed retrospectively. RESULTS: Of 482 patients, 143 (29.7%) underwent intestinal surgery with a median follow-up time of 8.6 years (range, 1-30.5). Kaplan-Meier survival estimates of the cumulative probability of CD-related intestinal surgery were 14.2% at 5 years and 24.5% at 10 years from diagnosis. Of these, 14% needed more than one operation. Multivariate Cox models showed that isolated ileal disease (hazard ratio [HR] 2.39, P = 0.008), complicated behavior (penetrating or stricturing) (HR 2.44, P < 0.001) and higher severity indices, at diagnosis, including Harvey-Bradshaw (HR 1.06, P = 0.009) and short Pediatric Crohn's Disease Activity Index (HR 1.02, P = 0.001) were associated with increased risk for intestinal surgery. Age, gender, family history of CD, early introduction of immunomodulators, treatment with anti-tumor necrosis factor α, or diagnosis before the year 2000 did not affect the risk of bowel surgery. CONCLUSIONS: Ileal location, complicated behavior, and higher disease activity indices at diagnosis are independent risk factors for bowel surgery, whereas anti-tumor necrosis factor α treatment and diagnosis during the "biological era" are not associated with diminished long-term surgical risk.

Evolution of disease phenotype in pediatric-onset Crohn's disease after more than 10 years follow up-Cohort study.

BACKGROUND: Pediatric-onset Crohn's disease (CD) is a heterogeneous disorder which is subjected to progression and complications in a substantial proportion of patients. AIMS: We aimed to assess the progression in pediatric-onset CD phenotype on long term follow up. METHODS: Medical charts of pediatric onset CD patients with at least 10 years follow-up were analyzed retrospectively. Disease phenotype was determined at diagnosis and during follow up at different time points. Phenotype was determined according to the Paris classification. The impact of possible predictors on phenotype progression was assessed as well as the association between different therapeutic regimens during disease course and phenotype progression. RESULTS: Progression of disease location, behavior, and perianal involvement was observed in 20%, 38% and 20% of patients, respectively, after a median follow-up of 16.4 (±4.4) years. Microscopic ileocolonic disease at diagnosis was significant predictors for progression of disease extent. Treatment with anti tumor necrosis factor-ɑ agents and number of flares per years of follow-up were associated with progression of disease extent, behavior and perianal involvement. CONCLUSION: Disease extent, behavior and prevalence of perianal disease change significantly over time in pediatric-onset CD. In our cohort, most clinical, laboratory and endoscopic parameters do not serve as predictors for long-term disease progression.

Food Intake Adequacy in Children and Adolescents With Inflammatory Bowel Disease.

OBJECTIVES: Diet assessment is essential in the care of patients with inflammatory bowel disease (IBD). We aimed to study food intake in children with IBD and evaluated the relation of dietary intake with disease activity and nutritional status in these children. METHODS: This cross-sectional study investigated 68 children and adolescents with IBD (57 Crohn disease, 11 ulcerative colitis). Evaluation included clinical, laboratory, and nutritional assessment including 3 days diet record. RESULTS: Compared with recommended daily allowance, the intake of patients with IBD was significantly poor for carbohydrates (75%, P = 0.016), calcium (49%, P < 0.05), magnesium (76%, P < 0.05), vitamin A (72%, P < 0.05), vitamin E (57%, P < 0.05), and fiber (44%, P < 0.05) and higher for protein (175%, P < 0.05), iron (112%, P < 0.05), and water-soluble vitamins (118%-189% P < 0.05). Compared with the intakes of healthy children from National Nutritional Survey, the intake of IBD group was lower for calories (78%, P = 0.012), carbohydrates (61% P < 0.05), magnesium (67% P < 0.05), vitamin C (34%, P < 0.05), and fiber (54%, P < 0.05) and high for B12 (141%, P < 0.05). Fifty subjects ate ordinary diets, 7 of 68 children were on exclusive enteral nutrition and 11 of 68 consumed regular food with different polymeric formulas supplements. Compared with children without supplements, children on exclusive enteral nutrition and nutritional supplements (18/68) had significantly better intakes of energy (1870 ±â€Š755 vs 2267 ±â€Š432, P < 0.05), carbohydrates (223 ±â€Š97 vs 292 ±â€Š99, P < 0.05), and all minerals (P < 0.05) and micronutrients (P < 0.05). Dietary intake was not different by disease status (remission or relapse). CONCLUSIONS: In the absence of nutritional supplements, food intake is inadequate for many nutrients in many children with IBD.

Validation of a Nutritional Screening Tool for Ambulatory Use in Pediatrics.

OBJECTIVES: To evaluate the use of Screening Tool for the Assessment of Malnutrition in Pediatrics (STAMP) in a primary health care clinic in the community and to assess the impact of its use on medical staff's awareness of nutritional status. METHODS: STAMP scoring system was tested as is and with modifications in the ambulatory setting. Nutritional risk according to STAMP was compared with a detailed nutritional assessment performed by a registered dietitian. Recording of nutrition-related data and anthropometric measurements in medical files were compared prior and post implementation. RESULTS: Sixty children were included (31 girls, 52%), ages between 1 and 6 years, mean age 2.8 ±â€Š1.5 (mean ±â€ŠSD). STAMP scores yielded a fair agreement between STAMP and the dietitian's nutritional assessment: κ = 0.47 (95% confidence interval [CI] 0.24-0.7), sensitivity of 47.62% (95% CI 28.34-67.63). Modified STAMP yielded more substantial agreement: κ = 0.57 (95% CI 0.35-0.79), sensitivity of 76.19% (95% CI 54.91-89.37), specificity of 82.05% (95% CI 67.33-91.02). The use of STAMP resulted in an increase in recording of appetite, dietary intake, and anthropometric measurements. CONCLUSIONS: Modification of the STAMP improved nutritional risk evaluation in community setting. The use of STAMP in a primary health care clinic raised clinician's awareness to nutritional status. Further work will identify whether this could be translated into lower malnutrition rates and better child care.

Parenteral Nutrition in Very Low Birth Weight Preterm Infants.

Parenteral nutrition (PN) must be initiated as soon as possible after delivery in very low birth weight (VLBW) preterm infants in order to prevent postnatal growth failure and improve neurodevelopmental outcome. When administered early, high levels of parenteral amino acids (AA) are well tolerated and prevent negative nitrogen balance. Although proteins are the driving force for growth, protein synthesis is energy-demanding. Intravenous lipid emulsions (ILE) constitute a good energy source because of their high energy density and provide essential fatty acids (FA) along with their long-chain polyunsaturated fatty acid (LC-PUFA) derivatives necessary for central nervous system and retinal development. Early supply of ILE is not associated with increased morbidity. No significant differences were found between ILE based on soybean oil only and mixed ILE containing soybean oil in combination with other fat sources, except for a reduction in the incidence of sepsis with non-pure soybean ILE, and possibly less PN-associated liver disease with mixed ILE containing some fish oil. In preterm infants glucose homeostasis is still immature in the first days of life and abnormalities of glucose homeostasis are common. VLBW infants may not tolerate high levels of glucose infusion without hyperglycemia. Administering lower levels of glucose infusion as part of full early PN seems more successful than insulin at this stage. Postpartum there is a transition period when the water and electrolyte balance may be severely disturbed and should be closely monitored. Avoiding fluid overload is critical for preventing respiratory and other morbidities.